Farrell Sandra A, Sodhi Sandi, Marshall Christian R, Guerin Andrea, Slavotinek Anne, Paton Tara, Chong Karen, Sirkin Wilma L, Scherer Stephen W, Bérubé-Simard Félix-Antoine, Pilon Nicolas
Department of Laboratory Medicine and Genetics, Trillium Health Partners, Mississauga, Ontario, Canada.
Genome Diagnostics, Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
Am J Med Genet A. 2017 Nov;173(11):3070-3074. doi: 10.1002/ajmg.a.38354. Epub 2017 Sep 12.
Isolated congenital diaphragmatic hernia is often a sporadic event with a low recurrence risk. However, underlying genetic etiologies, such as chromosome anomalies or single gene disorders, are identified in a small number of individuals. We describe two fetuses with a unique pattern of multiple congenital anomalies, including diaphragmatic hernia, short bowel and asplenia, born to first-cousin parents. Whole exome sequencing showed that both were homozygous for a missense variant, c.950A>C, predicting p.Asp317Ala, in the H.20-Like Homeobox 1 (HLX1) gene. HLX is a homeobox transcription factor gene which is relatively conserved across species. Hlx homozygous null mice have a short bowel and reduced muscle cells in the diaphragm, closely resembling the anomalies in the two fetuses and we therefore suggest that the HLX mutation in this family could explain the fetal findings.
孤立性先天性膈疝通常是偶发事件，复发风险较低。然而，在少数个体中可发现潜在的遗传病因，如染色体异常或单基因疾病。我们描述了两名患有多种先天性异常独特模式的胎儿，包括膈疝、短肠和无脾症，其父母为近亲。全外显子组测序显示，两人在H.20样同源框1（HLX1）基因中均为错义变体c.950A>C的纯合子，预测为p.Asp317Ala。HLX是一种同源框转录因子基因，在物种间相对保守。Hlx纯合缺失小鼠有短肠且膈肌中的肌肉细胞减少，与这两名胎儿的异常情况极为相似，因此我们认为该家族中的HLX突变可以解释胎儿的这些表现。
